UIP or not UIP Pattern: That is not the Only Question UIP or not UIP Pattern: That is not the Only Question! Stéphane Jouneau 11 July 2014 Respiratory Medicine Department, Pontchaillou Hospital, Rennes, France

Case Overview This case highlights how a usual interstitial pneumonia (UIP) pattern may be caused by a number of different pathologies, not just idiopathic pulmonary fibrosis (IPF). In order to make an accurate diagnosis of IPF, it is important to conduct a rigorous clinical primary examination to exclude other pathophysiological causes

Medical history and tests Initial visit (July 2012) Male, 67 years old 90 kg, 175 cm Ex-smoker: 15 pack-years Occupation: Former commercial delegate who travelled regularly to USA, China and North Africa; no history of environmental exposures

Medical history and tests Initial visit (July 2012) Comorbidities: Arterial hypertension, type 2 diabetes, coronary heart disease (stent in 2004), mesenteric infarction (1995) and arthrosis Current medications: Esomeprazole 20 mg, ramipril 5 mg, ASA 75 mg, metoprolol 200 mg, metformin 850 mg, gliclazide 60 mg and simvastatin 20 mg

Medical history and tests Initial visit (July 2012) Physical examination: Chronic productive cough (with mucopurulent sputum) and mild dyspnoea (New York Heart Association Stage I) but no asthenia, anorexia or fever Patient had a history of recurrent lower respiratory tract infections in the past 2 years Blood pressure 120/60 mmHg Heart rate 56 beats per minute SpO2 (room air) = 98% Bibasilar crackles on lung auscultation Hypereosinophilia = 1700/mm3

IMAGING HRCT scan (August 2012) Pattern recognised: Subpleural, basal predominance Reticular abnormality Honeycombing Absence of features listed as inconsistent with UIP pattern Conclusion = definite UIP pattern

Imaging – HRCT (Image 1) HRCT (August 2012) Definite UIP pattern with reticular abnormalities with a subpleural, basal predominance (arrows)

Imaging – HRCT (Image 2) HRCT (August 2012) Honeycombing with a subpleural, basal predominance (circles)

Imaging – HRCT (Image 3) HRCT (August 2012) Reticular abnormalities (arrows) and honeycombing (circles) with a subpleural, basal predominance

Imaging – HRCT (Image 4) HRCT (August 2012) Reticular abnormalities (arrows) and honeycombing (circles)

Imaging – HRCT (Image 5) HRCT (August 2012) Reticular abnormalities (arrows) and honeycombing (circles)

Imaging – HRCT (Image 6) HRCT (August 2012) Reticular abnormalities (arrows) and honeycombing (circles

Image subscript added, we have obtained the permission to use the image QuestionS Question 1 If a patient with the signs shown in the photo and a definite UIP pattern on chest CT-scan presents at the clinic complaining of bilateral joints and muscles pains, following a recent occurrence of Raynaud syndrome, what is the most probable diagnosis? Idiopathic pulmonary fibrosis Rheumatoid arthritis with ILD Diffuse erythematous lupus with ILD Anti-synthetase syndrome with ILD [correct answer] Jouneau S., et al. Les manifestations pulmonaires du syndrome des antisynthetases. Revue des Maladies Respiratoires, Elsevier Masson, 2014, in press. Used with permission of the Société de Pneumologie de Langue Française.

Answers Answer 1 Although there is a high variability in symptoms and severity, the presence of a number of extra-thoracic manifestations, such as myalgia or muscular deficit, Raynaud’s phenomenon, polyarthritis, fever, or mechanics hands in association with interstitial lung disease are all suggestive of antisynthetase syndrome.1,2 However, positive anti-RNA synthetase antibodies (anti-Jo1, anti-PL7, and anti-PL12) are required to confirm the diagnosis.1,2 1Solomon J, et al. J Bras Pneumol. 2011;37(1):100–109; 2Fischer A, et al. Respir Med. 2009;103(11):1719-24.

Lung function measurements (August 2012) Overall, lung function/gas exchange appeared to be good There were no signs of infection or connective tissue disease Results of bronchoalveolar lavage appeared normal; however, additional blood tests revealed an increasing eosinophil count A 6-minute walk test was not performed

Lung function measurements (August 2012) Parameter Value (% of predicted) FEV1/FVC 89% predicted FEV1 117% predicted FVC 98% predicted DLCO 62% predicted

Laboratory Laboratory results Blood eosinophil count: 2200/mm3 in August 2012; 2700/mm3 in September 2012 Parameter Results Antinuclear antibody Negative Rheumatoid factor Anti-cyclic citrullinated peptide antibodies Anti-neutrophil cytoplasmic antibodies

BRONCHOSCOPY Bronchoscopy results Normal bronchial tree with no macroscopic anomalies observed BAL differential cell count: Parameter Value Total cell count 3.4 × 106 cells/mL Alveolar macrophages 87% Lymphocytes 12% Neutrophils 1% Eosinophils 0% Normal BAL differential count, no hypereosinophilia on BAL

QuestionS Question 2 What would make you suspect another diagnosis other than IPF? Possible UIP pattern on chest CT-scan Probable UIP pattern on pulmonary histology Numerous long-term medications 42 year-old patient [correct answer]

Answers Answer 2 Because IPF is rare before the age of 50, the index of suspicion for an underlying connective tissue disease should be high.1 In such a young patient, you have to be very careful with the diagnosis of IPF. The patient should be promptly referred to a lung transplant centre and evaluated for specific telomerase mutations ie, SFPC, SFPB, GATA-2.2 1Spagnolo P, et al. Multidisciplinary Respiratory Medicine 2012;7:42; 2Savage S, and Bertuch A. Genetics in Medicine 2010;12:753–764.

Medical history and tests Follow-up (July 2013) Similar to on first presentation; however, the patient’s dyspnoea had worsened (New York Heart Association Stage II) Laboratory findings were also similar to those observed on initial presentation with the exception of the patient’s eosinophil count, which had increased 3500/mm3 in July 2013 5700/mm3 in September 2013 Raised suspicion of possible Churg-Strauss syndrome or parasitic infection such as aspergillosis, ascaridosis, lymphatic filariasis, distomatosis, trichinosis, toxocaris, strongyloides Also possibility of other connective tissue diseases e.g. rheumatoid arthritis or systemic lupus erythematosus

IMAGING HRCT scan (July 2013) Consistent with a definite UIP pattern, including Reticular abnormalities

Imaging – HRCT (Image 1) HRCT (July 2013) Reticular abnormalities

Imaging – HRCT (Image 2) HRCT (July 2013) Honeycombing

Imaging – HRCT (Image 3) HRCT (July 2013) Reticular abnormalities (arrows) and honeycombing (circles

Imaging – HRCT (Image 4) HRCT (July 2013) Reticular abnormalities (arrows) and honeycombing (circles

Imaging – HRCT (Image 5) HRCT (July 2013) Reticular abnormalities (arrows) and honeycombing (circles

Imaging – HRCT (Image 6) HRCT (July 2013) Reticular abnormalities (arrows) and honeycombing (circles

Lung function measurements (July 2013) Parameter Value (% of predicted) FEV1/FVC 86% predicted FEV1 105% predicted FVC 90% predicted TLC DLCO 57% predicted Parameter Value (absolute) pH 7.48 PaO2 92 mmHg PaCO2 35 mmHg CO2 24% SaO2 97% Slight decline in lung function from previous visit

Lung function measurements (July 2013) Results of 6-minute walk test (room air): 480 m without pause, no desaturation (100%  99%); Borg 2  3

Haematology results (September 2013) Laboratory Haematology results (September 2013) To exclude other causes such as Churg–Strauss syndrome or parasitic infections a myelogram, osteomedullar biopsy and medullary karyotyping were conducted All tests appeared normal Furthermore, and because there was a suspicion of hypereosinophilic syndrome the patient was genotyped Genotyping identified an FIP1L1-PDGFRα fusion gene

DIAGNOSIS HRCT scans revealed a UIP pattern suggestive of IPF; however, the patient’s lung function remained relatively stable throughout Laboratory tests revealed an increasing eosinophil count Following genotyping an FIP1L1-PDGFRα fusion gene was identified → The patient was diagnosed as having either IPF and hypereosinophilic syndrome or hypereosinophilic syndrome with lung fibrosis → Imatinib was initiated

Learnings from the case Demonstrates the importance of a thorough clinical examination, including physical examination, laboratory tests and blood work- up, and HRCT in the diagnosis of interstitial lung diseases Highlights that, in complex cases, a pulmonologist must also think like an internist and consider pulmonary manifestations of other diseases